Benlysta

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Mortality

There were more deaths reported with BENLYSTA than with
placebo during the controlled period of the clinical trials. Out of 2,133
patients in 3 clinical trials, a total of 14 deaths occurred during the
placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%),
0/111 (0%), and 6/674 (0.9%) deaths in the groups receiving placebo, BENLYSTA 1
mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg, respectively. No single cause
of death predominated. Etiologies included infection, cardiovascular disease,
and suicide.

Serious Infections

Serious and sometimes fatal infections have been reported
in patients receiving immunosuppressive agents, including BENLYSTA. Physicians
should exercise caution when considering the use of BENLYSTA in patients with
chronic infections. Patients receiving any therapy for chronic infection should
not begin therapy with BENLYSTA. Consider interrupting therapy with BENLYSTA in
patients who develop a new infection while undergoing treatment with BENLYSTA
and monitor these patients closely.

In the controlled clinical trials, the overall incidence
of infections was 71% in patients treated with BENLYSTA compared with 67% in
patients who received placebo. The most frequent infections ( > 5% of patients
receiving BENLYSTA) were upper respiratory tract infection, urinary tract
infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious
infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of
patients who received placebo. The most frequent serious infections included
pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections
leading to discontinuation of treatment occurred in 0.7% of patients receiving
BENLYSTA and 1.0% of patients receiving placebo. Infections resulting in death occurred
in 0.3% (4/1,458) of patients treated with BENLYSTA and in 0.1% (1/675) of
patients receiving placebo.

Progressive Multifocal Leukoencephalopathy (PML)

Cases of JC virus-associated PML resulting in
neurological deficits, including fatal cases, have been reported in patients
with SLE receiving immunosuppressants, including BENLYSTA. Risk factors for PML
include treatment with immunosuppressant therapies and impairment of immune
function. Consider the diagnosis of PML in any patient presenting with
new-onset or deteriorating neurological signs and symptoms and consult with a
neurologist or other appropriate specialist as clinically indicated. In
patients with confirmed PML, consider stopping immunosuppressant therapy, including
BENLYSTA.

Malignancy

The impact of treatment with BENLYSTA on the development
of malignancies is not known. In the controlled clinical trials, malignancies
(including non-melanoma skin cancers) were reported in 0.4% of patients
receiving BENLYSTA and 0.4% of patients receiving placebo. In the controlled
clinical trials, malignancies, excluding non-melanoma skin cancers, were
observed in 0.2% (3/1,458) and 0.3% (2/675) of patients receiving BENLYSTA and
placebo, respectively. The mechanism of action of BENLYSTA could increase the
risk for the development of malignancies.

Hypersensitivity Reactions, Including Anaphylaxis

Acute hypersensitivity reactions, including anaphylaxis
and death, have been reported in association with BENLYSTA. These events
generally occurred within hours of the infusion; however, they may occur later.
Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia,
headache, and facial edema, have been reported and typically occurred up to a
week following the most recent infusion. Hypersensitivity, including serious
reactions, has occurred in patients who have previously tolerated infusions of
BENLYSTA. Limited data suggest that patients with a history of multiple drug
allergies or significant hypersensitivity may be at increased risk. In the
controlled clinical trials, hypersensitivity reactions (occurring on the same
day of infusion) were reported in 13% (191/1,458) of patients receiving
BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was
observed in 0.6% (9/1,458) of patients receiving BENLYSTA and 0.4% (3/675) of
patients receiving placebo. Manifestations included hypotension, angioedema,
urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and
symptoms, it was not possible to distinguish between hypersensitivity reactions
and infusion reactions in all cases [see Infusion Reactions]. Some
patients (13%) received premedication, which may have mitigated or masked a
hypersensitivity response; however, there is insufficient evidence to determine
whether premedication diminishes the frequency or severity of hypersensitivity
reactions.

BENLYSTA should be administered by healthcare providers
prepared to manage anaphylaxis. In the event of a serious reaction,
administration of BENLYSTA must be discontinued immediately and appropriate
medical therapy administered. Patients should be monitored during and for an
appropriate period of time after administration of BENLYSTA. Patients should be
informed of the signs and symptoms of an acute hypersensitivity reaction and be
instructed to seek immediate medical care should a reaction occur.

Infusion Reactions

In the controlled clinical trials, adverse events
associated with the infusion (occurring on the same day of the infusion) were
reported in 17% (251/1,458) of patients receiving BENLYSTA and 15% (99/675) of
patients receiving placebo. Serious infusion reactions (excluding
hypersensitivity reactions) were reported in 0.5% of patients receiving
BENLYSTA and 0.4% of patients receiving placebo and included bradycardia,
myalgia, headache, rash, urticaria, and hypotension. The most common infusion
reactions ( ≥ 3% of patients receiving BENLYSTA) were headache, nausea, and
skin reactions. Due to overlap in signs and symptoms, it was not possible to
distinguish between hypersensitivity reactions and infusion reactions in all
cases [see Hypersensitivity Reactions, Including Anaphylaxis]. Some patients (13%) received
premedication, which may have mitigated or masked an infusion reaction;
however, there is insufficient evidence to determine whether premedication
diminishes the frequency or severity of infusion reactions [see ADVERSE
REACTIONS].

BENLYSTA should be administered by healthcare providers
prepared to manage infusion reactions. The infusion rate may be slowed or
interrupted if the patient develops an infusion reaction. Healthcare providers
should be aware of the risk of hypersensitivity reactions, which may present as
infusion reactions, and monitor patients closely.

Depression

In the controlled clinical trials, psychiatric events
were reported more frequently with BENLYSTA (16%) than with placebo (12%),
related primarily to depression-related events (6.3% BENLYSTA and 4.7%
placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA
and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients
receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4%
of patients receiving placebo. Serious depression was reported in 0.4%
(6/1,458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving
placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA. The
majority of patients who reported serious depression or suicidal behavior had a
history of depression or other serious psychiatric disorders and most were
receiving psychoactive medications. It is unknown if treatment with BENLYSTA is
associated with increased risk for these events.

Patients receiving BENLYSTA should be instructed to
contact their healthcare provider if they experience new or worsening
depression, suicidal thoughts, or other mood changes.

Immunization

Live vaccines should not be given for 30 days before or
concurrently with BENLYSTA as clinical safety has not been established. No data
are available on the secondary transmission of infection from persons receiving
live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new
immunizations. Because of its mechanism of action, BENLYSTA may interfere with
the response to immunizations.

Concomitant Use With Other Biologic Therapies Or Intravenous
Cyclophosphamide

BENLYSTA has not been studied in combination with other
biologic therapies, including B-cell targeted therapies, or intravenous
cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination
with biologic therapies or intravenous cyclophosphamide.

Patient Counseling Information

Advice For The Patient

Give patients the Medication Guide for BENLYSTA and
provide them an opportunity to read it prior to each treatment session. It is
important that the patient's overall health be assessed at each infusion visit
and any questions resulting from the patient's reading of the Medication Guide
be discussed.

Mortality: Advise patients that more patients
receiving BENLYSTA in the main clinical trials died than did patients receiving
placebo treatment [see WARNINGS AND PRECAUTIONS].

Serious Infections: Advise patients that BENLYSTA
may decrease their ability to fight infections. Ask patients if they have a
history of chronic infections and if they are currently on any therapy for an
infection [see WARNINGS AND PRECAUTIONS]. Instruct patients to tell
their healthcare provider if they develop signs or symptoms of an infection.

Progressive Multifocal Leukoencephalopathy (PML): Advise
patients to contact their healthcare professional if they experience new or
worsening neurological symptoms such as memory loss, confusion, dizziness or
loss of balance, difficulty talking or walking, or vision problems [see WARNINGS
AND PRECAUTIONS].

Hypersensitivity/Anaphylactic and Infusion Reactions:
Educate patients on the signs and symptoms of hypersensitivity and infusion
reactions, including wheezing, difficulty breathing, angioedema, rash,
hypotension, bradycardia, and headache. Instruct patients to immediately tell
their healthcare provider if they experience symptoms of an allergic reaction
during or after the administration of BENLYSTA. Inform patients to tell their
healthcare provider about possible reactions that may include a combination of
symptoms such as rash, nausea, fatigue, muscle aches, headache, and/or facial
swelling and may occur after administration of BENLYSTA [see WARNINGS AND
PRECAUTIONS].

Depression: Instruct patients to contact their
healthcare provider if they experience new or worsening depression, suicidal
thoughts or other mood changes [see WARNINGS AND PRECAUTIONS].

Immunizations: Inform patients that they should
not receive live vaccines while taking BENLYSTA. Response to vaccinations could
be impaired by BENLYSTA [see WARNINGS AND PRECAUTIONS].

Pregnancy and Nursing Mothers: Inform patients
that BENLYSTA has not been studied in pregnant women or nursing mothers so the
effects of BENLYSTA on pregnant women or nursing infants are not known.
Instruct patients to tell their healthcare provider if they are pregnant,
become pregnant, or are thinking about becoming pregnant [see Use in
Specific Populations]. Encourage pregnant patients to enroll in the
pregnancy registry for BENLYSTA [see Use In Specific Populations].
Instruct patients to tell their healthcare provider if they plan to breastfeed
their infant [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies have not been performed to
evaluate the carcinogenic potential of belimumab. The mutagenic potential of
belimumab was not evaluated.

Effects on male and female fertility have not been
directly evaluated in animal studies.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled clinical studies
using BENLYSTA in pregnant women. Immunoglobulin G (IgG) antibodies, including
BENLYSTA, can cross the placenta. Because animal reproduction studies are not
always predictive of human response, BENLYSTA should be used during pregnancy
only if the potential benefit to the mother justifies the potential risk to the
fetus. Women of childbearing potential should use adequate contraception during
treatment with BENLYSTA and for at least 4 months after the final treatment.

Nonclinical reproductive studies have been performed in
pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5, and 150 mg/kg
by intravenous infusion (the high dose was approximately 9 times the
anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150.
Belimumab was shown to cross the placenta. Belimumab was not associated with
direct or indirect teratogenicity under the conditions tested. Fetal deaths
were observed in 14%, 24%, and 15% of pregnant females in the 0, 5 and 150
mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8%,
and 5%. The cause of fetal and infant deaths is not known. The relevance of
these findings to humans is not known. Other treatment-related findings were
limited to the expected reversible reduction of B cells in both dams and
infants and reversible reduction of immunoglobulin M (IgM) in infant monkeys.
B-cell numbers recovered after the cessation of belimumab treatment by about 1
year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM
levels in infants exposed to belimumab in utero recovered by 6 months of age.

Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women
exposed to BENLYSTA, a pregnancy registry has been established. Healthcare
professionals are encouraged to register patients and pregnant women are
encouraged to enroll themselves by calling 1-877-681-6296.

Nursing Mothers

It is not known whether BENLYSTA is excreted in human
milk or absorbed systemically after ingestion. However, belimumab was excreted
into the milk of cynomolgus monkeys. Because maternal antibodies are excreted
in human breast milk, a decision should be made whether to discontinue
breastfeeding or to discontinue the drug, taking into account the importance of
breastfeeding to the infant and the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of BENLYSTA have not been
established in children.

Geriatric Use

Clinical studies of BENLYSTA did not include sufficient
numbers of subjects aged 65 or over to determine whether they respond
differently from younger subjects. Use with caution in elderly patients.